11-66871780-GT-CA

Variant names:

• chr11-66871780-GT-CA
• NM_001040716.2:c.227_228delACinsTG
• PC p.His76Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001040716.2(PC):​c.227_228delACinsTG​(p.His76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H76H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PC NM_001040716.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.57
• Publications: 0 publications found

Genes affected

PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

PC Gene-Disease associations (from GenCC):

• pyruvate carboxylase deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women's Health, Labcorp Genetics (formerly Invitae), G2P
• pyruvate carboxylase deficiency, benign type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, infantile form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, severe neonatal type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040716.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PC	NM_001040716.2	MANE Select	c.227_228delACinsTG	p.His76Leu	missense	N/A	NP_001035806.1	P11498-1
	PC	NM_000920.4		c.227_228delACinsTG	p.His76Leu	missense	N/A	NP_000911.2	P11498-1
	PC	NM_001439352.1		c.227_228delACinsTG	p.His76Leu	missense	N/A	NP_001426281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PC	ENST00000393960.7	TSL:5 MANE Select	c.227_228delACinsTG	p.His76Leu	missense	N/A	ENSP00000377532.1	P11498-1
	PC	ENST00000393955.6	TSL:1	c.227_228delACinsTG	p.His76Leu	missense	N/A	ENSP00000377527.2	P11498-1
	PC	ENST00000393958.7	TSL:1	c.227_228delACinsTG	p.His76Leu	missense	N/A	ENSP00000377530.2	P11498-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-66639251;